MPN updates from iwMDS-iwMPN 2024 | Unmet needs in MF and focusing on early intervention in patients with MPNs

Naveen Pemmaraju:

Hi, everyone. I’m Naveen Pemmaraju, professor of leukemia at MD Anderson in Houston, Texas. I’m here at a very important meeting, the iwMPN/MDS meeting, and I’m joined by my colleagues, Dr. Abe Yacoub from Kansas, Dr. Aaron Gerds from the Cleveland Clinic and Professor Claire Harrison from the UK.

We had an outstanding, scintillating session on unmet needs in the myeloproliferative neoplasms, and in this discussion, we really were able to talk about thought-provoking items such as new endpoints in our disease. I’m going to turn to each of my colleagues to feature them to give a quick summary and to give us one or two unanswered questions that remain.

First, we’ll start with Dr. Abe Yacoub who talked to us about pre-fibrotic MF. Abe?

Abdulraheem Yacoub:

Yeah, thank you very much, Dr. Pemmaraju.

So pre-fibrotic myelofibrosis is an evolving diagnosis in myelofibrosis as a subcategory of primary myelofibrosis. It’s a disease that generally is perceived to be lower risk than fibrotic-phase myelofibrosis and has a slower progression to more advanced diseases. However, it still results in significant morbidity and loss of life for patients with that diagnosis. We still do not have clear understanding of how this is distinguished from the mainstream myelofibrosis, and we do not have necessary guidelines that drive us into how do we approach these patients. Those patients have been categorically excluded from clinical trials.

So hopefully we will design more purposeful efforts to try to target these patients specifically and provide them with therapy that would alter their future. It is a window-of-opportunity disease in which you see a disease that is slowly evolving in which you can offer the patients therapy that has the time to impact their outcomes.

Naveen Pemmaraju:

Oh, wonderful. Thank you for that summary.

Dr. Gerds, you talked about a very important topic, huge in the clinic for our patients and for our providers, which is that of thrombocytopenia in myelofibrosis. What are your thoughts on that?

Aaron Gerds:

Yeah, thrombocytopenia is a prevalent problem. At least half the patients will have thrombocytopenia within the first year of diagnosis, and if patient’s thrombocytopenia gets so severe, you’re doing transfusions just to support their platelet counts and prevent serious bleeding from happening.

On the flip side, it’s prognostic, too. So it’s not only prevalent, it’s prognostic for worse outcomes. The increasing degree of thrombocytopenia is associated with the worsening survival. And that’s not just for bleeding events, either. I mean, that includes progression in other forms of death that can occur in our patients. So it’s definitely kind of a canary-in-the-coal mine for really, really bad disease.

But I think there’s really a practical part to thrombocytopenia. So you’ve got these patients, you’re worried they’re going to that awful head bleed or some other bleeding complication or just be burdened with a bunch of petechiae and nosebleeds, which is it’s a nuisance, but it’s significant nuisance.

And then you combine that with really our best effective therapies are transplant, which is not always available for every patient, or platelet transfusions. And certainly here in the United States, we are in a crisis with our blood banks. There is not enough blood to go around. There are certainly not enough platelets to go around. I think the Red Cross calls me about every other day to donate platelets, I feel like. So I think it’s a severe unmet need.

That’s in combination with few drugs that actually can improve platelet counts. In my talk I talked about maybe danazol can do that to some degree. Things like TPO mimetics have been looked at. The IMiDs like pomalidomide, there are some responses there, but this goes hand-in-hand with some toxicity. So really there aren’t a lot of agents that focus on ameliorating thrombocytopenia in these patients. And I think we’re heavily reliant on the prospect of drugs that, dare I say, will deeply modify disease to remedy that.

But we really need to, I think in the interim, focus on things that can improve platelet counts, and I think the major challenge with that is the fact that the megakaryocyte is the cell of disease. Those are the cells that are going to be making the platelets, but they’re also the ones that are truly, truly diseased. So I think it doubles the challenge there to making thrombocytopenia better for our patients.

Naveen Pemmaraju:

Oh, wonderful. So both of you, thanks for your summary.

So from pre-fibrotic MF, to the thrombocytopenia in MPNs, specifically MF, now to Claire’s topic, sort of the exciting factors that you mentioned, which is are there novel agents, Claire, that we can think about beyond the JAK/STAT pathway, the only approved class of drugs in our field? You mentioned one of the most exciting in our field, that of pelabresib, the novel BET inhibitor. Claire, if you can summarize those results for the folks out there?

Claire Harrison:

I think that where we need to try to go in the field is to intervene early, and I think this is something that was touched on in several sessions in this meeting, and I think it’s a brave move to take on JAK inhibitor monotherapy, still using a JAK inhibitor and adding something else.

So we discussed today data from a couple of trials. The one that specifically you’ve asked me to talk about now is pelabresib, which is a bromodomain or BET inhibitor. And in a precursor study with monotherapy add-back and then a small cohort of JAK inhibitor-naive patients, we’ve seen that this agent can benefit patients. I think it’s important to know that these agents can do that as a monotherapy so when you go to adding into the JAK inhibitor that you do believe the signal that you see.

So we shared some updates today from the MANIFEST-2 study, which is a JAK inhibitor-naive study, including a lot of intermediate one-risk patients according to the DIPSS score. Meeting, like the study that you presented, Naveen, that maybe we can turn to you to talk about in a moment, doubling the number of SVR35 responses, having probably equivalent symptom responses, so that’s only week 24, doubling the number of patients that had both spleen and symptom responses, and then doing that generally safely. Looking at some other interesting biological responses, so VAF reduction, fibrosis reduction, changes in megakaryocyte, and I didn’t show it because I wanted to stick to time, but also erythrocyte recovery mirrored in hemoglobin. But the kind of $64 million question is how do we put all of this together and demonstrate benefit for patients?

So I would really like us to stop looking at symptoms as a primary endpoint. Maybe we just need to look at non-inferiority for symptoms and then start looking at durability of response, depth of response. But to do that requires a lot of effort and a lot of collaboration with pharma to pool this data.

But I believe that over time we will demonstrate that combinations are better for patients. I can’t see us moving away from a JAK inhibitor for a while. But Naveen, maybe you can share with us the beautiful data you shared. You had a big job because you were talking about three different agents.

Naveen Pemmaraju:

That’s right. And thank you, Claire, for your summary because as you mentioned, the pelabresib agent, not only exciting, but well-tolerated, a very nice safety profile, again, in a double oral combination.

As you mentioned, I also showed data on the TRANSFORM-1 study. That’s the navitoclax, the oral BCL-XL/BCL-2 agent that you and I had the chance to develop early on in the Phase I/II studies. Again, as you mentioned with pelabresib, it also, the navitoclax showed activity pre-clinical single-agent add-on to RUX, and then ultimately in RUX combination front line. We took that into the Phase III randomized global study, the TRANSFORM-1 study, 252 patients enrolled, intermediate-2 risk and high-risk patients, 80% or more were intermediate-2 risk, almost half had high molecular risk mutations including a third of those ASXL1. We showed similar results to what you mentioned, doubling of the SVR35, 60+ percent versus 30% in the RUX placebo arm and also some early indications of VAF reduction, as we showed in the presentation.

The drug was fairly well-tolerated. It did have some cytopenias as a signal. The vast majority of patients will get thrombocytopenia, considered to be a BCL-XL effect. Also patients will have GI side effects including nausea, vomiting, diarrhea. So those dose reductions were part of the study. There were no clinically significant bleeding events that led to anything with the modulations in the platelets. So overall, out of 252 patients, 60-plus percent SVR reduction, SVR35 at week 24.

But yet, as Claire mentioned, the overall statistical significance was not there for the symptoms. So the two groups, there was no P-value that was significant. So even though the primary endpoint of both of these studies was met, the secondary and all-comers was not. So the question for our field, Claire and team here, is what do we do now? What’s next? Aaron?

Aaron Gerds:

If I could echo a point that you made, Dr. Harrison, is this concept of putting your best foot forward almost. So we have the TRANSFORM, we have MANIFEST-2 like really saying, “Okay, this is the place where these things are really going to move the field forward.” We have historical precedence for this. We think about interferons, and interferons seemed to shine the best in pre-fibrotic myelofibrosis and ET and PV before the disease gets advanced. Then there was a presentation earlier in the day, so this again is a recurring theme throughout the morning, about the prospect of CAR T-cells and engineered T-cells in cellular therapies. They seem to do better earlier on. When the disease becomes very advanced and more mutated and other things pop up, it just doesn’t work. Maybe down-regulation of the CALR-mutant, calreticulin, the TPO receptor, whatever, but putting our best foot forward.

So I think we really need to keep that in mind when we are looking at these new therapies, not just relegating to like sixth-line therapy in patients who have been heavily pretreated because it’s probably not going to shine as brightly as it should. And we owe it to every one of our patients to really get every possible therapy out there and tested in the right way in order so we don’t lose any opportunities.

Claire Harrison:

I also think there’s something about treating early. So as I talked to new patients, and there was a great session on young patients this morning, and I also love that in the patient that you presented. You know, if these patients had breast cancer, would we be saying to them, “Gosh, I want to wait until you’ve got stage 3 disease before I treat you because you’ve got a 2% risk of…” I mean, it’s a bit insane. We have well-tolerated agents. These combinations that we’ve spoken about today are well-tolerated. Interferon is well-tolerated. I think it’s time for change. There are some patients that I probably wouldn’t treat upfront. I think triple-negative ET, if I can’t find any mutation, I think that’s probably not something I would treat.

Abdulraheem Yacoub:

There’s evidence that if patients are actually on that discussion platform and having to weigh in on their choices, most of them actually choose to invest in a therapy that is more effective, even if there’s an uphead initial risk, as long as they know that the long-term benefit of this would outweigh any short-term side effects. So if patients get to weigh in on this, which they always should, I think they probably will make decisions that are similar to your opinion.

Aaron Gerds:

I think a similar experience, the trial was mentioned earlier this morning, but the CALRmut calreticulin vaccine study. So it’s a calreticulin and a JAK2 vaccine all in one, boosted with ipilimumab. You know, ipilimumab has some toxicity. But with that trial at our center, we had a bevy of patients with lowish risk disease who were really interested in this. They’re like, “Yeah, I know my time horizon is measured in decades and not months, but here’s this idea that I could turn back the clock on my disease and it’s so attractive.”

We also saw, over and over again, this disconnect between docs and patients on what they want of their treatment. The disconnect between, “I want to prevent progression, but my doc is really just worried about my platelet count numbers” kind of a thing. I think that’s partly on us because we just don’t have the effective therapies yet and we really, again, got to reframe ourselves. Okay, we got to have this long horizon in our mind. We got to put our best foot forward and keep pushing for that direction.

Claire Harrison:

We also need to demonstrate, so what I loved about your case was, you showed the CALR VAF going down. Over and over today, we’ve been discussing VAF reduction, but the evidence is only really there for JAK2. So we need to, in advance of having these therapies, and an antibody infusion once or twice a year, if it keeps the disease in a kind of minimal state, could be really beneficial for patients. But we need to gather the data so that we can provide that evidence to the FDA or others that if you do reduce the VAF, you reduce the risk of progression of disease, et cetera. Otherwise, we will never get these therapies.

Naveen Pemmaraju:

And just to add to the spectrum that you guys are nicely discussing, we were talking about early intervention. How about early, early intervention? We heard about CHIP earlier today in the meeting. So if we think of our spectrum now at least of JAK2, from JAK2-mutant CHIP, which we learned is either the fourth or fifth most common CHIP, to then pre-fibrotic MF, ET, PV, over early MF, late-stage MF, maybe our dream of early disease modification can finally happen, as we start to elucidate these earlier categories before the patient has had a chance to accumulate all of these other mutations. Wow. Claire?

Claire Harrison:

So I put a question mark about wanting to put ET and PV right back to a CHIP, right?

Naveen Pemmaraju:

Yes, right, right.

Claire Harrison:

Because is it just enough that we get to like 10%? Because the beautiful data from Jean-Jacques about being able to stop a therapy, minimize the therapy, and then not forgetting about inflammation, not forgetting about… It’s all very well to do that, but if your patient’s still smoking and they’re overweight and they’re hypertensive, et cetera, we’re not doing them any favors, and those factors also play into clonal progression as well. So I think targeting a stem cell pool that is not mutated is not reasonable for most of our patients. Just putting it out there.

Naveen Pemmaraju:

Well, what a wonderful discussion, colleagues, friends. I really enjoyed hearing your talks in this discussion. So thanks to the VJHemOnc team for allowing us this fantastic medical education platform. Follow us online and on social media. Thanks, everyone.